I have no idea who reads Chemiotics II, or what their backgrounds are. I do know that the people who comment are quite sophisticated in molecular biology, protein chemistry etc. etc. For some reason, Chemiotics II recently made the following list: http://www.onlinedegrees.org/25-best-chemistry-blogs-for-college-students/ I don’t want to leave anyone behind, and I certainly didn’t know any of this stuff in college (’56 – ’60), much of it bering unknown, hence the reason for this post.
Most of the drugs docs use work by binding to proteins (which I assume you know a reasonable amount about) altering their structure and function in some way. Here are a few examples of interest to premeds (and hopefully the rest of you).
Curare is the generic term for poisons used by tribes of neuropharmacologists in South America on their arrows to kill prey. D-tubocurarine (D-Tc) is one such curare. It has a beautiful structure which the budding organic chemists among you should look up. D-Tc works by binding to the protein receptor for acetyl choline in muscle and preventing its action (which is to conduct sodium ions into the muscle cell so it can contract). Prey can’t move (or breathe). D-tc is a classic example of an antagonist drug. It blocks the normal effect of the normal ligand of the protein. One true story about curare is just too good to pass up.
Interns don’t get much sleep. On my 3 month surgery rotation back in ’67 it was 36 hours on and 12 off, but to get a weekend off, call was bunched so that in one 7 day stretch it was 5 nights on 2 nights off making 24/168 hours off call. Most nights we got 3 – 4 hours of crummy sleep. My wife, knowing conversation was hopeless, took the kids to her parents that week. According to legend, Mary Walker was one such intern, who in 1934 fell asleep during a lecture on myasthenia gravis (a disease characterized by muscle weakness, which can affect the ability to breathe, hence the gravis) for which there was no known treatment. She woke up after the lecture, walked up to the great man and asked how to treat myasthenia. The great man, irritated, said — “It’s just like curare poisoning”, so she went off to the library, looked up curare poisoning, found the treatment for it (physostigmine), administered it to a myasthenic, and became famous.
40 years ago, L-DOPA was released in the USA for the treatment of Parkinsonism (the subject of a future post). At the brain capillary, an enzyme (L-DOPA decarboxylase) removes the carboxyl group, forming dopamine inside the brain, which binds to (at least 5 different) protein receptors for it, causing a variety of effects in the neurons carrying them (which we’re still trying to figure out in detail). Dopamine is a classic example of an agonist, something which binds to a receptor causing an appropriate physiologic effect.
So drugs antagonizing dopamine should produce a state resembling Parkinson’s disease. They do. Such drugs should never be used, right? Wrong ! The first drugs useful against schizophrenia and other psychoses (the phenothiazines, haloperidol) did exactly that. We’re still trying to figure out how they work (and better ways to treat these diseases).
Not all drugs are agonists or antagonists. The benzodiazepines (xanax, librium, valium, etc. etc.) and the barbiturates bind to a protein receptor for gamma amino butyric acid (the GABA[A] receptor). Unlike D-Tc which binds to the place acetyl choline wants to bind on its receptor and is thus a competitive antagonist, these drugs bind to a second site on the GABA[A] receptor, causing a conformational change, which makes the receptor more responsive to its natural ligand (gamma amino butyric acid). This conformational change is called an allosteric effect and the place on the protein where these drugs bind is called an allosteric site. Allosteric effects can be either positive, as in the example above, or negative.
The classic negative allosteric drug is strychnine. It binds to yet another receptor in the brain and spinal cord (this time for glycine, a neurotransmitter like acetylcholine and dopamine). Glycine is an inhibitory neurotransmitter, meaning it calms down neurons and makes them less likely to fire. Strychnine poisoning is characterized by painful muscle spasms which can be mistaken for seizures. Strychnine binds to a site on the glycine receptor distinct from that bound by glycine and causes a change in receptor conformation making glycine ineffective as an inhibitor, so this is a negative allosteric effect. Since the binding site is different, strychnine is a noncompetitive antagonist of glycine.
I saw a case of strychnine poisoning as an intern. It wasn’t from a suicidal ingestion, but in an addict. Most nitrogen containing drugs from plants (called alkaloids because they are alkaline) have a bitter taste. Morphine is one such alkaloid, and narcotic addicts sometimes taste what they are sold, because dealers ‘cut’ the amount of drug in what they say they are selling to make more money. Dealers sometimes would add strychnine (another alkaloid) to what they were selling to give it the bitter taste (and fake out the addict). Dealers have several ways of getting rid of troublesome customers. One is to give them pure morphine (or whatever they’ve been taking) which gives the addict a much higher dose than they were used to, causing respiratory depression and death. Another (the present case) is to give them strychnine. The muscle spasms in this patient were spectacular, but not seizures, because the patient was conscious throughout. They were coming from spinal cord glycine receptors gone wild.
The body uses allosteric effects all the time. One final example. 2, 3 diphosphoglyceric acid is produced by glycolysis (a way to break down glucose without using oxygen). The amount of energy released from glucose using oxygen is much (more than 10 times) higher. So 2, 3 diphosphoglyceric acid is a signal that the tissue producing it isn’t getting enough oxygen. It binds to hemoglobin causing an allosteric change in structure so that the hemoglobin more readily gives up its remaining oxygen.
Slick isn’t it? Isn’t medicine fascinating? You don’t have a prayer of really understanding this stuff without a solid background in organic chemistry (which is reason #532 why I think premeds should take and pass organic).
Unfortunately, we’re lightyears from understanding medicine as well as we understand chemistry. This is where you come in.
Chemiotics II 
Comments
You may want to describe the modern view of antagonists and agonists; while slightly more complicated than the “classical” view it is now widely accepted. This is the description of proteins existing in an active and inactive conformation (or multiple such conformations). Agonists selectively stabilize the active conformation while antagonists stabilize the inactive one (strictly speaking, antagonists stabilize both conformations while inverse agonists stabilize the inactive one, but we can leave that out for now)
One problem in blogging is that you have only a vague idea of your audience. In this case I had a fairly clear idea of who I was writing for (college students). I’ve audited several college and grad school courses, but I still don’t have a clear idea of how much molecular biology and medicine they know. So I decided to explain what I didn’t know when I was in college long ago.
There is an awful lot of information in the post for someone approaching it for the first time. What you say about agonists and antagonists is of course correct, but I decided to leave it out given the audience I was writing for.